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Prostanoids and Hair Follicles

Prostanoids and Hair Follicles

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV orders. relevance inthe treatment andprevention of hairdis­ Thishaspotential the underlyingmechanisms. clinical ontheir differentandopposing hairgrowth effects and of on receptors inhairfollicles,focussing metabolism of and the expression pattern doi: 10.2340/00015555-2843 growth, hairfolliclecycle, and hairdisorders. to advancesinresearchinto prostanoidsandhairfollicle their metabolisminhairfollicles, withparticularregard This review discusses the biosynthesis ofprostanoids and largely throughadverse events andcasereports(3,4). ween prostanoids and hair follicles has been investigated bet relationship the and responses, inflammatory and inflammation on focused has prostanoids on Research nal, cardiovascular, and genitourinary systems (1,2). systems, includingtheimmune,respiratory, gastrointesti tive synthases. Prostanoids modulate many physiological P hotmail.com Medical University, Shenyang 110001 China. E-mail: hongduochen@ Corr: Hong-Duo Chen, Department of Dermatology, No. 1 Hospital of China Acta DermVenereol 2018;98:318–323. Accepted Nov 13,2017;EpubaheadofprintNov 14,2017 gue; hairfollicle. analo PGF2α ; Key words: prostanoid; sely, PGD tect fromradiation-induced hairloss inmice.Conver ted to PGD by cyclo-oxygenase, to PGH2, which is then conver sequential metabolism of acid,catalysed arachidonic pathologicalProstanoids contexts. aregeneratedby coids that modulate many physiological systems and boxane A Prostanoids, including (PGs) and throm- Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang, China Xue-Gang XU andHong-Duo CHEN Disorders Prostanoids andHairFollicles:Implications forTherapyofHair 318 Acta DermVenereol 2018;98: 318–323 The PGF suggests evidence that prostanoids play a role in regulating hair growth. Recent synthases. specific their growth of human eyelashes. PGE growth ofhumaneyelashes. approved in theUSand routinely toused enhancethe sequential actionsofcyclo-oxygenase(COX)andrespec by phospholipases(PLAs),followingmetabolismviathe of arachidonicacidfromtheplasmamembranecells The biosynthesisofprostanoidsbeginswiththerelease acid andotherlong-chainpolyunsaturatedfattyacids(1). rostaglandins (PGs)andthromboxane A termed prostanoids and are derived from arachidonic termed prostanoidsandarederivedfromarachidonic 2α 2 2 analogue isFood andDrugAdministration- inhibits hairgrowth. Thispaperreviewsthe (TXA 2 , PGE 2 ), areafamily of lipid-derived auta 2 , PGF 2α , PGI 2 andTXA 2 isreported to pro 2 , catalysed by , catalysed This isan open access article under the CC BY-NC license. www.medicaljournals.se/acta 2 (TXA REVIEW ARTICLE 2 ) are ) are ------

then transformed into different PGsand TXA (EP receptor; FP:PGF (DP TXA TXA coupled receptors. The 5typesofprostanoids, PGE G-protein- specific through hormones local paracrine focusses onotherPGs.Prostanoidsactasautocrine/ mics andcardiovascularfunctions;thereforethisreview ced by mitogenic and pro-inflammatory stimuli. PGH to different effects to hair follicles. PDF receptors and G-protein, trigger different second messengers and lead G protein-coupled receptors. Different prostanoids can bind different biological effects on hair follicles via activating different cell surface of the Fig. 1.Schematic biosynthesis of prostanoids and their hair loss. COX1: cyclo-oxygenase 1; COX2: cyclo-oxygenase 2; PGG antagonists can inhibit DP2 activation. All have treatment potential for PGD PGI COX-1 isconstitutivelyexpressed,whileCOX-2indu both ofwhich can transform into PGH2. There are2mainCOXisoforms,COX-1andCOX-2, PROSTANOID METABOLISM prostaglandin G generated by different synthases. The mainlybioactiveprostanoids due tothefactthattheybinddifferent receptorsand have different, oreven opposing, properties, possibly receptor (TP) respectively ( PGI 2 2 2 synthase; TXA receptor; DP1: PGD 1 synthase; PGES: PGE 2 1 , EP , PGD , DP 2 . TXA Journal Compilation ©2018ActaDermato-Venereologica. 2 , EP 2 ), PGF in vivoincludePGE 2 , PGF 2 2 2 ; PGF ischaracterizedasmodulatinghaemodyna ; PGH 3 2α , EP receptor;IP:PGI 2 : A 2α 2α 2 2α : prostaglandin H 4 : (FP),andthromboxane A ), PGI , and TXA , 2 receptor 1; DP 2 synthase; PGFS: PGF 2 receptor(IP),PGD Fig. 1). Different prostanoids 2 receptor. 2 ; PGD 2α 2 2 , PGI , bindtoPGE analogues can activate FP. DP2 2 2α ; TxAS: TXA 2 ; PGI : PGD 2 : prostaglandin D 2 , PGD 2 2 : prostaglandin I receptor 2; EP: PGE 2α 2 synthase; PGIS: synthase; PGDS: 2 , PGF 2 2 2 , catalysed , catalysed receptors receptors 2 2α ; PGE , and 2 ; TP: 2 is is 2 2 2 - - 2 2 : : ,

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV comprising epithelialandmesenchymalcells. The struc Anatomically, thehairfollicleisanintricatemini-organ HAIR FOLLICLE BIOLOGY a broadarrayofdiseases(Fig.1). antagonistic effects inmany physiologicalsystemsand characteristics mightexplaintheirsynergistic and/or as afunctionofligandconcentrationorstructure. These G-protein-coupled signallingpathwaysmayalsochange also beenreported. The effects ofprostanoidsonthese has pathway β-catenin the and signalling receptor EGF betweentheFP (1).Cross-talk expression to COX-2 and FP andboththecross-activationofEP andFP canlead mechanism. However, inhighconcentrations,PGF couple tothesmallG-proteinRhoviaaGq-independent also can FP receptor The (2). flux calcium intracellular DP: dermalpapilla; IRS: inner rootsheath; ORS: outerrootsheath. also activate EP2. High concentration PGE be dividedintoapermanent upperpartandatransient are alsorichlyinnervated. In general,hairfolliclescan blood supply flows to the hair follicles, and hair follicles the hairfollicleispartof pilosebaceousunit. A rich with thesebaceousglandand thearrectorpilimuscle, an innerrootsheath,andthehairshaft(7). Together sheath, root outer an sheath, tissue connective fibrous ture ofhairfolliclesfromoutsidetoinsideincludes a activation post-PGD DP1/DP2 mayaccountfordifferent signallingpathway logy. The expressionpatternofL-PGDS/H-PGDSand flux. PGD protein, whichleadstoinhibitionofcAMP andcalcium cellular cAMP and calcium flux.DP2 triggersGi-type G (5). This reviewfocussesmainlyonPGD have different signallingpathwaysinduction(Table I ) Table I.Expressionpatternandsignaltransductionofprostaglandin(PG)receptors mediator, dependingonthediseaseprocessandaetio distribution (6).PGD sequence, structure,cellularlocalizationandtissue differ biochemicallywithrespecttofeaturessuchas PGDS) and haematopoietic PGDS(H-PGDS). These protein-coupled adenylate cyclase, which increases intra receptors, DP1andDP2(2).triggersGs-typeG- which aremorecloselyrelatedtohairgrowth. G binds to a single receptor, FP. Activation of FP leads to PGI PGE PGD Class PGF q There are2PGD -type G protein mediated IP 2 2α 2 2 2 can act as either a pro- or anti-inflammatory DP2 EP4 EP3 EP2 DP1 FP IP EP1 Subtype 2 2 production.UnlikePGD synthases,lipocalinPGDS(L- 2 canbindandactivate2distinct All epithelial compartments of epidermis and hair follicle (+/–) Epidermis (+, cytoplasmic expression), hair follicles (+),DP (+/–) Epidermis (+, nuclear expression), hair follicles (+), DP (++) Epidermis (+, perinuclear expression), hairfollicles (+), DP (++) Basal layer of epidermis (+/–) hair follicle ORS (+) Epidermis (–), most haircompartments (+) hair shaft cuticle cells (+),epidermis(+/–) Basal cells of epidermis(+),hairfollicles (+), DP (++) Expression pattern 3 generation and increased generationandincreased 2 2 can activate andPGF 2 , PGF 2α can can 2α 2α - - - ,

adult skinwerealsoCOX-1 positive,whichmightindi and inthedistalportionof hairfollicleofneonataland 7-week-old mice.Dendritic cells locatedinterfollicularly skin throughday28afterbirth, aswellintheskinof E15–E18, andthispatternof expressionwasdetectedin granular keratinocytesofthesuprabasalcompartmentat mouse dorsalskin.COX-1wasdetectedinspinousand spatiotemporally expressedduringmorphogenesisof Decker et al. (13) demonstrated that COX isozymes were protein barely was COX-2 detectable (12). Müller- epidermis and the upper part of the hair follicle, whereas isoform expressedinkeratinocytesoftheinterfollicular In amousetelogenskinmodel,COX-1wasthemajor RECEPTORS INHAIR FOLLICLES PROSTANOIDS ANDPROSTANOID cycling. hair disordersarerelatedtoaberrationsinfollicle and wound-induced “scarring” alopecia, most patients’ years (10,11). Exceptforrarecongenitalhairdisorders follicles growlongbecausetheystayinanagenfor2–6 phase of eyelash hair follicles is 1–4 months, while scalp follicles ofeyebrowisonly2–4weeksandtheanagen hair folliclesareshortbecausetheanagenphaseof example, human eyebrow hair follicles and eyelash of hairsisproportionaltothedurationanagen.For on the location and type of hair follicle. The final length shed daily. The durationoftheentirehaircycledepends in catagen, and 14% intelogen, and 70–100 hairs are 84% ofthehumanscalphairfolliclesareinanagen,2% cycles. Underphysiologicalconditions,approximately differs from many other mammals with synchronous hair part. The haircycleinhumansisasynchronous,which migrate tothelowerpartregeneratecycling produce their descendants, which actively proliferate and anagen, bulge stem cells in the permanent part transiently generated byapoptosisduringcatagen. At theonsetof cate a role of COX-1 in the skin immune system. COX-2 cate aroleofCOX-1intheskin immunesystem.COX-2 proximal outer root sheath (transient lower part) are de and hairshedding(exogen)(7,9). The hairmatrixand (anagen), follicleregression(catagen),rest(telogen), The hairfolliclecycleconsistsofstagesgrowth the hair cycle and their biological characteristics (8). lower cyclingpart,basedontheirdifferences during Gi Gs Gi, G12 Gs Gs Gq Gs Gq G-protein-coupled Prostanoids andhairfollicles Acta DermVenereol 2018 cAMP$ cAMP# cAMP$ cAMP# cAMP# IP cAMP# IP Second messenger 3 3 /DAG/Ca /DAG/Ca , Ca , Ca , Ca 2+ 2+ 2+ 2+ 2+ # # # , Rho # # , Rho 319 - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV www.medicaljournals.se/acta functional significance of the expression of these pro these of expression the of significance functional differ indifferent tissuesor species. Although theexact expression patternofdifferent prostanoidreceptorsmay in eyelashes in the anagen phase (15). Therefore, the of thebulbandstemeyelashesexpressedonly FP waslocatedpredominantlyintheinnerrootsheath immunohistological study of human eyelids, finding that layer anddermalpapilla(5).Nesheretal.performedan (5). FP expressionwasrestricted totheORScompanion the haircuticlelayerandORSbasallayer, respectively indicating thatthePGD gen and PGD2 was produced via 1 versely, IP andDP They claimed that Ptgds was first expressed in late ana that PGD2peakedaftertheapexofPtgdsexpression. known markerofcatagenonset). They furtherdiscovered (a 5 factor growth fibroblast of pattern expression the anagen andwasmuchhigherthanintelogen,similarto during hair cycles and found that et al.(14)measuredtheexpressionlevelofPtgdsmRNA volved inhairgrowthanddifferentiation control.Garza and cPGES, whichcatalysePGH mPGES-2 mPGES-1, expressed human hairfollicles in humanhairfollicles. Their experimentsrevealedthat the expression profile of key of PG metabolism been reported(Table I).Colombeetal.(13)investigated stanoid receptor distributioninhumanhair follicles have may contributetoPGproductionandhairfolliclebiology. follicle morphogenesisandhaircycling,which and COX-2arespatiotemporallyexpressedduringhair (12). As thekeyreactioninPGbiosynthesis,COX-1 declined, and was barely detectable in telogen follicles (12). expression When folliclesenteredcatagen,COX-2 basal outerrootsheath(ORS)andsebaceousglandcells licles afterbirth,COX-2expressionbecamerestrictedto of earlystagehairfolliclesintofullydifferentiated fol thegradualtransition During during hairmorphogenesis. appeared in all cells of elongated hair germs and hair pegs 320 AKR1C3/PGFS, whichconvertsPGH These observationssupporttheconceptthatPGsarein and whole hair follicles (Table SI shown awidespectrum of expressioninculturedcells present inhairfollicles(5).Mostofthesereceptorshave follicles hasbeenfound(14). presence of PTGDS in the non-permanent regionof hair arrector pilimuscle.Inhumanhairfollicles,asimilar late anagen in the keratinocytes of the ORS below the techniques on mouse skin tissue, Ptgds was evident in apoptotic catagenstage.Usingimmunohistochemistry EP involved severalhairfolliclecompartments(5).Con https://www.medicaljournals.se/acta/content/abstract/10.2340/00015555-2843 Several studies on prostanoid metabolism andpro metabolism onprostanoid studies Several All oftheprostanoidreceptorshavebeenreportedas 2 , EP X-G. XuandH-D.Chen 3 , EP 4 , DP 2 1 , and TP and,toalesserextent,EP were more specifically expressed in 2 pathwaydirectlyinductedthe Ptgds during catagen, 2 1 Ptgds peaked in late toPGE ). The expression of 2 toPGF 2 , aswell 2α (13). 1 ------, clinical ratings,digitalimageanalysis,andpatient-repor eyelash hypotrichosis has been well documented, with of treatment the in of safety and efficacy in enhancement of eyebrow thickness, with fewer side- minoxidil as efficacious equally was bimatoprost that eyelash hypotrichosis(Fig.1, of treatment the for analogue PGF2α approved (FDA) in thetreatmentofeyelashandeyebrow AA (18,19). Ross EK et al. reported no efficacy of topical by 45%ofsubjects(17).However, Faghihietal.and margins, andtotalormoderateresponseswerereported latanoprost 0.005%ophthalmicsolutionintheireyelid treated withinjectionsoftriamcinoloneacetonideand survey ofsubjectswithalopeciaareata(AA)universalis increased hairdensity. Coronel-Pérezetal.conducted a showed sites thelatanoprost-treated placebo-treated sites, mini-zones ofthescalp. Compared with the baseline and were treatedwith0.1%latanoprostandplaceboontwo AGA (Hamilton-NorwoodpatternsofbaldnessII–III) hair densityandpigmentation(16).Sixteenmenwith increased significantly latanoprost 0.1% of application with mildandrogeneticalopecia(AGA)showedthatthe treated eye.Recently, aplacebo-controlledtrial inmen ture, andpigmentationwereobservedinthelatanoprost- skin. Increasedhairnumbers,length,thickness,curva and lowereyelid,aswellvellushairoftheeyelid eyelashes andregionalintermediatehairsoftheupper tanoprost, hypertrichosisinvolvedtheipsilateralterminal in 1997 (3). In 43 patients receiving unilateral topical la first documented as a hair-growth stimulant by Johnstone of PGanaloguesinglaucomatreatment.Latanoprostwas grew longer asasideeffect following topicalapplication first noted in the observation that eyelashes and eyebrows The potentialroleofPGsinthetreatment ofalopecia was PROSTAGLANDIN-INDUCED HAIR GROWTH involved inhairbiology. prostanoid receptorssupporttheideathatprostanoidsare on hairgrowth. All theseobservationsofprostanoidsand PGF2α of effect the to related is papilla dermal in sion biological effects ofsomePGs,suchashowFP expres stanoid receptorsremainsunclear, itdoesexplainsome induced hypotrichosis(Table SI eyebrows, eyebrowhypotrichosis, andchemotherapy- prost inotherhairdisorders, includingthinningofthe and observationshavealso reportedtheuseofbimato for atleast12monthswassafe(25).Manyclinicaltrials a patientsatisfactionlevelof92.5%,andlong-termuse 0.03% bimatoprostforeyelashhypotrichosisrevealed recent retrospectivereviewof585subjectstreatedwith resulted inahigheroccurrenceofeyelashgrowth. A application ofophthalmicbimatoprostsolution(0.03%) cal studyshowedthat,compared with latanoprost, the ted measuresofsatisfaction(Table SI Bimatoprost is the only Food and Drug theonlyFoodandDrug Bimatoprost is Administration Table SI 1 ). One study showed showed study ). One 1 ) (23–26). A clini 1 ) (20–22). The ) ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV studies ofPG-inducedhair growth,theunderlyingme because ofpotentialside-effects. and Drug Administration (FDA) categoryCmedicine Food a as classified is bimatoprost reported, been have tests, andasthenia. Although nofoetalmalformations ratory tractinfection,headache,abnormalliverfunction documented. Systemicside-effects includeupperrespi been also uveitis andherpeticsimplexviralinfectionhas perpigmentation oftheeyelids(31). The association of PGF whether confirm to suggested are medication of tration sample size,longerstudyduration,andhigherconcen been “negative”. Therefore, morestudieswithalarger or poorlycontrolled,andthecontrolledstudieshave However, these “positive” studies were uncontrolled cells ortooseverealopecia,amongotherreasons(31). without eyelashes, irreparable damage of follicle stem ures weredue to inadequate penetration ofhairfollicles authors havequestionedwhetherthesetreatmentfail not inthepost-chemotherapyor AA subgroups.Some vehicle wereevidentamongthehealthyadolescents,but study. Significant treatment benefits with bimatoprost vs. parallel-group multicentre, randomized,double-masked, induced eyelashhypotrichosisandhealthycontrolsina (33) enrolled 71adolescents with chemotherapy- or AA- al. et Borchert patients. any in changes significant no investigator-masked, controlledstudy, showed which 11 eyelash AA patients in a 16-week, randomized, in the treatment of AA. Roseborough et al. (32) enrolled bimatoprost of efficacy no indicated reports However, ceptable cosmeticresponsewith0.03%bimatoprost(30). 43.24% ofpatientswith AA universalisachievedanac tive (29–31). A 1-yearretrospectivestudyindicatedthat alopecia areata(AA) and chemotherapy-inducedeyelashhypotrichosis(28). effective andwelltoleratedinpatientswith idiopathic bimatoprost ophthalmicsolution0.03%for1yearwas parallel-group studyshowedthatdailytreatmentwith effects (27). A multicentre, double-blinded,randomized, eye irritation,drysymptoms,anderythemahy side-effects areeyepruritus,conjunctivalhyperaemia, local andsystemicside-effects. The mostcommon local safe, patientsshouldbeinformedaboutandmonitoredfor of thesetrialresults. of bimatoprostin AGA willbereportedonpublication gov) (Table SI Health Clinical Trials database(https://clinicaltrials. are currentlyregisteredintheUSNationalInstitutesof Numerous clinicaltrialsonusingbimatoprostin AGA failed to respond to injected 0.03%bimatoprost solution. female-pattern androgeneticalopecia (AGA) patientwho needs furtherstudy. Emeretal.(34)reporteda caseof application ofbimatoprostinthetreatment AGA Despite thepublicationof many clinicalreportsand for bimatoprost topical of safety and efficacy The Although latanoprost and bimatoprost are generally 2α analoguesareeffective intreatmentof AA. The 1 ) and the results on efficacy and safety and efficacy on results the and ) has beencontroversialornega also ------activity, hasbeenproposedasthemechanismof theef cutaneous blood flow and stimulation of dermal papilla though potassiumchannelopening,leadingtoincreased fect ofminoxidilonhairgrowthiswellknown.Even topical medicineforthetreatmentof AGA. The ef FDA-approved first the was Minoxidil (39). alopecia has been shown to protect mice from radiation-induced effects,hypertrichosis (38).PGE suchastravoprost the durationofanagenphase. catagen follicles,suggestingthatbimatoprostextends of anagenfolliclesandadecreaseintelogenlate proportion greater significantly a demonstrated group phase ofthehaircycle(37). The bimatoprost-treated a into classified was eyelid each of follicle hair Every were compared with mice treated with vehicle control. 0.03% ophthalmologicalsolutiononcedailyfor14days study usingamurinemodel,micereceivingbimatoprost anagen phasewithin8daysoftreatment(36).Inone suggested thattelogenfolliclesareinductedintothe melanogenesis (35).Mousestudiesoflatanoprosthave anagen, increased hair bulb thickness, and increased treatment arebelievedtoresultfromlongerdurationof chanisms arelargely obscure. The effects ofbimatoprost the alopeciawasduetoelevated COX-2activity. Müller- inhibitor) restoredhairgrowth, furtherindicatingthat mice. Administration of (a selective COX-2 glands were also observed in the K14-COX-2 transgenic skin, pyknoticnuclei,and enlargement ofsebaceous which presentedwithdistinct alopecia. Atrophy ofthe COX-2 underthecontrolofhumankeratin14promoter, generated atransgenicmousemodelthatoverexpressed foci exhibitingsignsofdysplasia(42).Boletal.(43) found hyperplasiainthescaleepidermisoftailwith follicle density, sebaceousglandhyperplasia,andpro led todelayedhairfolliclemorphogenesis,reduced baceous unit. The constitutive overexpression ofCOX-2 basal cells of the interfollicular epidermis and the pilose keratin 5promotertodirectCOX-2expressioninthe heterozygous transgenicmousemodelusingabovine of hairdysregulation.Neufangetal.(42)developeda dels have been developed with characteristic phenotypes hair growthhavenotbeengivenattentionuntilrecently. by evidence.However, theinhibitingeffects ofPGson That PGs stimulate hair growth has long been confirmed PROSTAGLANDIN-INHIBITED HAIR GROWTH on hairgrowth. PGs of effects stimulating the confirming further 41), stacyclin synthesisbycultureddermalpapillacells(40, increasing theproductionofPGE also suggestedthatminoxidilenhanceshairgrowthby of actiononhairgrowthisuncertain(40).Studieshave fect ofminoxidilonhairgrowth,itsexactmechanism Studies havealsoreportedotherPGanalogueswith Several COX-2over-expression transgenicmouse mo Prostanoids andhairfollicles Acta DermVenereol 2018 2 andinhibitingpro 321 ------2 Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV www.medicaljournals.se/acta haired scalpofmenwith AGA (14).Duringnormalfol they also confirmed that PGD that confirmed also they neogenesis (WIHN)asamarkerofskinregeneration, and not through DP1. Using wound-induced hair follicle hair growthinpatientswith AGA thatresearchersbe neogenesis (44). Exogenous application ofPGD inhibition mediatedbyPGD reported thatDP2antagonistsreversedthehairgrowth strain-matched controlmice.Recently, Zhengetal.(45) DP2 nullmiceshowedincreased WIHN comparedwith confirmed that PGD their inhibitoryeffect etal.further Garza onhairgrowth. immediately beforetheregressionphase,suggesting topical application of PGD that confirmed further They proliferation. keratinocyte by reducingPGD2-triggeredapoptosisandmaintaining diverse actions on hair growth and signalling profiles. signalling and growth hair on actions diverse out, moredetailedstudiesare neededtounderstandtheir and prostanoid receptors in hair follicles has been carried pathways. Although research on theroleofprostanoids sing effects onhairfolliclesthroughdifferent signalling Different prostanoidsmay havedifferent orevenoppo CONCLUSION tion andtreatment(Fig.1). exploration oftherolePGD established. Basedontheseresults,wecanconcludethat rone anddihydrotestosteroneasdriversof AGA is well PGD tinocytes, which initially set up the connection between creased WIHN inwild-typemice andthePGD licle cyclinginmice,PtgdsandPGD PTGDS andPGD of elevation the reported first al. et Garza growth. hair gan topayattentiontheinhibitingeffects ofPGsin ween PGsandinhibitionofhairgrowth. on theCOX-2expressionpatternandPGE development ofalopecia(12).However, furtherstudies the suppressed inhibitor COX-2 specific the with tivity also observed,andinhibitionoftransgenicCOX-2ac cycle. Alopecia andsebaceousglandhyperplasiawere stage and asubsequentdisturbanceofthehairfollicle COX-2 induced a precocious entry into the first catagen control ofkeratin5promoter. The overexpressionof overexpressionunderthemouse modelwithCOX-2 Decker etal.(12)describedahomozygoustransgenic 322 PGD hair germpopulation.Manteletal.(46)reportedthat did notsucceedinclarifyingtheexactrelationshipbet verified that PGD extended theanagenphase.Flowcytometryanalysis into catageninamousemodel,whileDP2antagonists of DP2 is a potential approach for hair disorder preven via the DP2receptor and in pharmacological antagonists It wasnotuntilPGD 2 2 enhanced testosterone metabolism in human kera andtestosteronemetabolism. The roleoftestoste X-G. XuandH-D.Chen 2 decreasedKi67 2 inthebaldscalp compared withthe 2 inhibitedhairgrowththroughDP2 2 was confirmed as inhibiting as confirmed was 2 2 resulted in accelerated entry in a dose-dependent manner inadose-dependentmanner 2 ininhibitinghairgrowth 2 decreased hairfollicle + cells in the secondary cellsinthesecondary 2 levelsincrease 2 metabolism 2 receptor 2 de ------13. 10. 15. 12. 17. 16. 14. 11. 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